We propose three aims to explore respiratory influences on sympathetic vasoconstrictor activity, blood flow distribution and limb muscle fatigue during exercise in health and disease. AIM A: The COPD patient experiences flow limitation and increased elastic work of breathing during exercise, often accompanied by limb muscle fatigue and exercise intolerance. We will relieve much of the exercise-induced respiratory muscle work (using a proportional assist mechanical ventilator) or arterial hypoxemia in COPD patients and determine their influence on quadriceps fatigue and limb muscle blood flow and vascular conductance. This work is a clinical translation of our recent research in healthy subjects showing significant effects of reducing the work of breathing or preventing arterial O2 desaturation during high intensity exercise on limb muscle fatigue, blood flow and performance. AIM B: We will use multiple flow probes in a chronically instrumented canine, to determine how exercise influences the distribution of blood flow between inspiratory, expiratory and limb locomotor muscles. We will examine the influence of changes in respiratory muscle work, of activating the limb metaboreflex via vascular occlusion, and the relative effects of local adrenergic agonists and antagonists on vascular conductances in the limb vs. diaphragm vs. expiratory muscles during exercise. In light of the hyperventilation and heightened sympatho-excitation in the CHF patient during exercise, we will also determine how and why the available cardiac output is distributed between limb and respiratory muscles during exercise in the canine model with CHF (induced by cardiac pacing). AIM C: We will use healthy and CHF canine models to determine the contribution of the carotid chemoreceptors to sympathetic restraint of blood flow to the exercising limb muscles. Given our preliminary findings that carotid chemoreceptors account for about one-third of the total sympathetic constraint on limb vascular conductance during even mild intensity exercise in the healthy dog, we will use denervation of the sympathetic innervation of the chemoreceptors to determine if chemoreptor sensitivity is reset during exercise via sympathetically mediated vasoconstriction. In summary, our goal is to gain insight into the contributions of respiratory muscle work, arterial O2 content and the carotid chemoreceptors to the distribution of cardiac output during exercise in health, COPD and CHF and the resultant effects on muscle fatigue and performance. [unreadable] [unreadable] [unreadable]